The lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid. The enzyme 5-lipoxygenase converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes (LT's).
Similarly, 12- and 15-lipoxygenase convert arachidonic acid to 12- and 15-HPETE, respectively. The biochemical reduction of 12-HPETE leads to 12-HETE, while 15-HPETE is the precursor of the class of biological agents known as the lipoxins.
A variety of biological effects are associated with these products from lipoxygenase metabolism of arachidonic acid and they have been implicated as mediators in a number of disease states. For example, the leukotrienes LTC.sub.4 and LTD.sub.4 are potent constrictors of human airways in vitro, and aerosol administration of these substances to nonasthmatic volunteers induces broncho-constriction. LTB.sub.4 and 5-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They also have been found in the synovial fluid of patients suffering from rheumatoid arthritis. Leukotrienes have also been implicated as important mediators in allergic rhinitis, psoriasis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, and ischemia-induced myocardial injury, among others. The biological activity of the leukotrienes has been reviewed by Lewis and Austeen, J. Clinical Invest. 73: 89 (1984) and by J. Sirois, Adv. Lioid Res. 21: 78 (1985).
The product, 12-HETE, has been found in high levels in the epidermal tissue of patients with psoriasis. The lipoxins have recently been shown to stimulate elastase and superoxide ion release from neutrophils.
Thus, the lipoxygenase enzymes are believed to play and important part in the biosynthesis of mediators of asthma, allergy, arthritis, psoriasis, and inflammation. Blocking these enzymes interrupts the biochemical pathways believed to be involved in these disease states.
One of the problems associated with the development of compounds which inhibit lipoxygenase is that many such compounds are poorly absorbed into the blood stream if administered orally. Thus, it is difficult to achieve high blood plasma levels of these drugs. Another deficiency of many lipoxygenase inhibitors is that, even when they are absorbed into the blood stream, they are often metabolized and do not have long plasma lifetimes. Metabolic processes convert the compounds into metabolites which are believed to have little or no lipoxygenase inhibitory action. Thus, there is a need for the development of lipoxygenase inhibiting compounds which are readily absorbed into the blood stream with attendant high blood plasma levels, and which have long plasma lifetimes.